"Alzheimer's disease" ("AD") is the term used to describe one of several "dementing disorders," brain diseases that progressively lead to loss of mental and physical functions, regardless of the age of onset. The cause(s) of AD remain(s) unknown. See, e.g., R. D. Teny, J. Neuropathol. Exper. Neurol. 55, 1023 (1996); D. J. Selkoe, Science 275,630 (1997).
AD is a major health-care problem. About 3 to 5 percent of older people suffer from the disease. A small fraction of Alzheimer's patients, i.e., persons suffering from AD, are under 50 years of age. Most are over 65. About 1 percent of the population aged 65-74 has the disease, increasing to about 5 percent of those aged 75-84 and to about 20 percent of those 85 or older. At least half the people in U.S. nursing homes have AD. The annual cost of caring for individuals with AD in institutional and community settings in the U.S. is about $40 billion for direct costs alone. As the population ages, the number of Alzheimer's patients and the costs of their care will rise as well.
In some cases, genetics plays a role in the risk of developing the disease. Thus, there are cases of familial Alzheimer's, in which related individuals are more likely to develop the disease because of common genetic factors. A genetic basis has been identified through the discovery of several genetic markers on chromosomes 1, 14 and 21 for a small subgroup of families in which the disease has frequently occurred at relatively early ages (beginning before age 50). Some evidence points to the gene on chromosome 19 for a protein, Apolipoprotein E ("Apo-E"), as implicated in certain other families that have frequently had the disease develop in family members at later ages; in these people, the gene encodes one particular variant, Apo-E4, of the several known variants of the Apo-E protein. Almost all persons who suffer from Down's Syndrome, which is caused by having three, rather than the normal two, copies of chromosome 21, develop Alzheimer's disease if they live to at least age 50. Alzheimer's disease is much more common among older women than older men. At age 80, the frequency of Alzheimer's disease among women is twice that among men. At age 90, the frequency among women is six times that among men.
Certain environmental factors are also thought to play a role in the development of the disease. High concentrations of aluminum may increase the risk of developing the disease. It is known that the incidence of the disease is lower among smokers than among non-smokers, leading to speculation that this is due to cholinergic activation by (-)--nicotine.
Alzheimer's disease can be diagnosed postmortem from microscopic abnormalities found in brain tissue. See "Consensus Recommendations for the Postmortem Diagnosis of Alzheimer's Disease," in Neurobiology of Aging (in the press), pre-published on the World-wide Web at the site for the Alzheimer Research Forum at http://www.alzforum.org/members/forums/consensus/index.html. The two principal abnormalities are senile or neuritic plaques (chemical deposits consisting of degenerating nerve cells combined with a form of protein called beta amyloid) and neurofibrillary tangles (malformations within nerve cells). The brains of AD patients of all ages reveal these abnormalities on autopsy examination. The plaques found in the brains of people with AD appear to be made, in part, from protein molecules--amyloid precursor protein ("APP")--that normally are essential components of the brain. Plaques are made when an enzyme snips APP apart at a specific place and then leaves the fragments--beta amyloid--in brain tissue where they come together in abnormal deposits. It has not as yet been definitely determined how neurofibrillary tangles are formed. Other abnormal anatomical and chemical changes associated with the disease have also been found. These include nerve-cell degeneration in the brain's nucleus basalis of Meynert and reduced levels of the neurotransmitter acetylcholine in the brain. But from a practical standpoint, the "classical" plaque and tangle changes seen in the brain at autopsy typically suffice for a diagnosis of AD. In fact, it is still only through the postmortem study of brain tissue from a person who was thought to have AD that a definitive diagnosis of the disorder can be made.
Brain scans, by one or more of computer-assisted tomography, positron-emission tomography, single photon emission computerized tomography, magnetic-resonance imaging and the like are known to be useful to discern changes characteristic of Alzheimer's disease in living patients as these changes become more evident with progression of the disease. These methods can also be useful in distinguishing from Alzheimer's disease certain other disorders that mimic Alzheimer's disease and might be reversible with appropriate treatment.
There are certain biochemical diagnostic "markers" that suggest that a person has or is developing AD and that can be detected without a brain biopsy while the person is living. Tests based on markers for the presence of or susceptibility to the disease are being developed. Among these markers are the occurrence in cerebrospinal fluid of elevated levels of the tau protein that occurs in lesions in the brains of persons with AD and the occurrence of mutations in the genes for two of the proteins that make up the cytochrome oxidase complex in mitochondria of persons with AD. Some of these markers can be detected even before behavioral manifestations of the disease become apparent in a person in whom AD is developing.
"Clinical" features of AD, which can be used, alone or together with brain scanning techniques or assays for biochemical markers, to diagnose possible or probable AD in patients antemortem, are threefold: (1) dementia--significant loss of intellectual abilities such as memory capacity, severe enough to interfere with social or occupational functioning; (2) insidious onset of symptoms--subtly progressive and irreversible course with documented deterioration over time; (3) exclusion of all other specific causes of dementia by history, physical examination, laboratory tests and psychometric and other studies.
Based on these three criteria, the clinical diagnosis of AD has been referred to as "a diagnosis by exclusion," and one that can only be made in the face of clinical deterioration over time. There is no specific clinical test or finding that is unique to AD. Hence, a diagnosis of AD is made by systematically excluding or "ruling out" all other disorders that can bring on symptoms similar to those of Alzheimer's.
Because of the many other disorders that can be confused with AD, a comprehensive clinical evaluation offers the best chance of arriving at a correct diagnosis of symptoms that might indicate AD. Such an evaluation includes at least three major components: (1) a thorough general medical workup, which should include a detailed medical history, blood work, urinalysis, chest x-ray, electroencephalogram, computerized tomography scan, and electrocardiogram; (2) a neurological examination; and (3) a psychiatric evaluation that may include psychological or psychometric testing. See also, Diagnostic and Statistical Manual of Mental Disorders, 4.sup.th Edition, American Psychiatric Association, Washington D.C., U.S.A. (1994).
It is estimated that about 10% of persons diagnosed as having AD in fact do not have that disease but rather have another disease which has similar symptoms. Tragically, some of these other diseases may be treatable if diagnosed. But first they must be identified and not dismissed as AD or "senility."
Conditions that affect the brain and result in intellectual, behavioral, and psychological dysfimction are referred to as "organic mental disorders." These disorders represent a broad grouping of diseases and include AD. Organic mental disorders that can cause clinical problems like those of AD, and which might be reversible or controlled with proper diagnosis and treatment, include the following:
Side Effects of Medications: Unusual reactions to medications, too much or too little of prescribed medications, combinations of medications which, when taken together, cause adverse side effects.
Substance Abuse: Abuse of legal and/or illegal drugs, alcohol abuse. PA1 Metabolic Disorders: Thyroid problems, nutritional deficiencies, anemias, etc. PA1 Circulatory Disorders: Heart problems, strokes, etc. PA1 Neurological Disorders: Normal-pressure hydrocephalus, multiple sclerosis, etc. PA1 Infections: Especially viral or fungal infections of the brain. PA1 Trauma: Injuries to the head. PA1 Toxic Factors: Carbon monoxide, methyl alcohol, etc. PA1 Tumors: Any type within the skull--whether originating or metastasizing there.
In addition to organic mental disorders resulting from these diverse causes, other forms of mental dysfunction or mental health problems can also be confused with AD. For example, severe forms of depression can cause problems with memory and concentration that initially may be indistinguishable from early symptoms of AD. Sometimes these conditions, referred to as "pseudodementia," can be reversed. Other psychiatric problems can similarly masquerade as AD and, like depression, respond to treatment.
In many cases, if a treatment or preventative for Alzheimer's would be available, a person diagnosed as likely having Alzheimer's but possibly having another disease or disorder with similar characteristics could be treated for both to be sure that the person is treated effectively.
Heretofore, only a limited number of pharmacological agents have been identified as effective in treating symptoms of AD in a person suffering therefrom. The most prominent of these today are tacrine and donepezil hydrochloride, which are cholinesterase inhibitors active in the brain. These drugs do not slow the progress of the disease. Other such cholinesterase inhibitors are being investigated for treating symptoms of the disease, as are certain cholinergic channel modulators (compounds which modulate functions of brain acetylcholine receptors).
No compound has been established as effective in blocking the development or progression of AD, although a number of compounds are thought to possibly have this capability and are being investigated for therapeutic use for this purpose. These compounds include the hormone estrogen, the non-steroidal anti-inflammatory ibuprofen, the anti-Parkinson's disease monoamine-B oxidase inhibitor selegiline (L-deprenyl), vitamin E, the compound propentofylline that stimulates release of nerve growth factor and inhibits reuptake of adenosine as a neurotransmitter, and the compound sabeluzole which is an antagonist of glutamate as a neurotransmitter and apparently is neuroprotective on account of stabilization of the neuronal cell cytoskeleton.
The present invention relates to levels in humans (as measured, for example, in serum) of the pituitary gonadotropins ("Gn's") follicle-stimulating hormone ("FSH") and luteinizing hormone ("LH"). It is known that these hormones are produced in response to gonadotropin releasing hormone ("GnRH"), which is also known as luteinizing hormone releasing hormone ("LHRH"). In the absence of GnRH, LH and FSH will not be made. Through a complex mechanism, sustained presence of high levels of GnRH will result in reduction in the levels of LH and FSH to the point that they have no detectable physiological activity (which means, for purposes of this application, that their levels are not detectable). Similarly, sustained presence of inhibin will result in reduction in the level of FSH to the point that it has no detectable physiological activity.
Not only GnRH but also the many known, physiologically active analogs thereof, some of which are agonists of GnRH, result in reduced levels of the gonadotropins, even to the point of indetectability, when they are maintained at physiologically active levels over sufficiently long periods of time. Similarly, inhibin and the many known physiologically active analogs thereof, some of which are agonists and others of which are antagonists of inhibin, result in reduced levels of FSH, even to the point of indetectability, when they are maintained at physiologically active levels over sufficiently long periods of time.
Reference herein to "GnRH analogs" means both GnRH and physiologically active analogs thereof. Reference herein to "inhibin analogs" means both inhibin and physiologically active analogs thereof.
It is also known that administration to a human of vaccines that cause production of antibodies that react with GnRH and inhibit its activity results in reduction, potentially to the point of indetectability, of FSH and LH.
Still further, administration to a human of vaccine-stimulated antibodies that react with FSH and LH inhibit the hormone's physiological activity, potentially to the point of indetectability.
Heretofore, no association has been recognized between AD and the level of LH or FSH. More specifically, it has not been recognized that reducing levels of Gn's will inhibit or prevent the development or progression of AD.